A Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial of Oral Brincidofovir for Cytomegalovirus Prophylaxis in Allogeneic Hematopoietic Cell Transplantation
Francisco M Marty, Drew J Winston, Roy F Chemaly, Kathleen M Mullane, Tsiporah B Shore, Genovefa A Papanicolaou, Greg Chittick, Thomas M Brundage, Chad Wilson, Marion E Morrison, Scott A Foster, W Garrett Nichols, Michael J Boeckh, SUPPRESS Trial Clinical Study Group, Francisco M Marty, Drew J Winston, Roy F Chemaly, Kathleen M Mullane, Tsiporah B Shore, Genovefa A Papanicolaou, Greg Chittick, Thomas M Brundage, Chad Wilson, Marion E Morrison, Scott A Foster, W Garrett Nichols, Michael J Boeckh, SUPPRESS Trial Clinical Study Group
Abstract
Cytomegalovirus (CMV) infection is a common complication of allogeneic hematopoietic cell transplantation (HCT). In this trial, we randomized adult CMV-seropositive HCT recipients without CMV viremia at screening 2:1 to receive brincidofovir or placebo until week 14 post-HCT. Randomization was stratified by center and risk of CMV infection. Patients were assessed weekly through week 15 and every third week thereafter through week 24 post-HCT. Patients who developed clinically significant CMV infection (CS-CMVi; CMV viremia requiring preemptive therapy or CMV disease) discontinued the study drug and began anti-CMV treatment. The primary endpoint was the proportion of patients with CS-CMVi through week 24 post-HCT; patients who discontinued the trial or with missing data were imputed as primary endpoint events. Between August 2013 and June 2015, 452 patients were randomized at a median of 15 days after HCT and received study drug. The proportion of patients who developed CS-CMVi or were imputed as having a primary endpoint event through week 24 was similar between brincidofovir-treated patients and placebo recipients (155 of 303 [51.2%] versus 78 of 149 [52.3%]; odds ratio, .95 [95% confidence interval, .64 to 1.41]; P = .805); fewer brincidofovir recipients developed CMV viremia through week 14 compared with placebo recipients (41.6%; P < .001). Serious adverse events were more frequent among brincidofovir recipients (57.1% versus 37.6%), driven by acute graft-versus-host disease (32.3% versus 6.0%) and diarrhea (6.9% versus 2.7%). Week 24 all-cause mortality was 15.5% among brincidofovir recipients and 10.1% among placebo recipients. Brincidofovir did not reduce CS-CMVi by week 24 post-HCT and was associated with gastrointestinal toxicity.
Keywords: Allogeneic hematopoietic cell transplantation; Antiviral; Brincidofovir; CMX001; Cytomegalovirus; Prophylaxis.
Copyright © 2018. Published by Elsevier Inc.
Figures
References
- Boeckh M, Nichols WG, Papanicolaou G, Rubin R, Wingard JR, Zaia J. Cytomegalovirus in hematopoietic stem cell transplant recipients: current status, known challenges, and future strategies. Biol Blood Marrow Transplant. 2003;9:543–558.
- Ljungman P, Hakki M, Boeckh M. Cytomegalovirus in hematopoietic stem cell transplant recipients. Infect Dis Clin North Am. 2010;24:319–337.
- Boeckh M, Ljungman P. How we treat cytomegalovirus in hematopoietic cell transplant recipients. Blood. 2009;113:5711–5719.
- Green ML, Leisenring W, Stachel D, et al. Efficacy of a viral load-based, risk-adapted, preemptive treatment strategy for prevention of cytomegalovirus disease after hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2012;18:1687–1699.
- Craddock C, Szydlo RM, Dazzi F, et al. Cytomegalovirus seropositivity adversely influences outcome after T-depleted unrelated donor transplant in patients with chronic myeloid leukaemia: the case for tailored graft-versus-host disease prophylaxis. Br J Haematol. 2001;112:228–236.
- Boeckh M, Nichols WG. The impact of cytomegalovirus serostatus of donor and recipient before hematopoietic stem cell transplantation in the era of antiviral prophylaxis and preemptive therapy. Blood. 2004;103:2003–2008.
- Marty FM, Bryar J, Browne SK, et al. Sirolimus-based graft-versus-host disease prophylaxis protects against cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation: a cohort analysis. Blood. 2007;110:490–500.
- Ljungman P, Brand R, Hoek J, et al. Donor cytomegalovirus status influences the outcome of allogeneic stem cell transplant: a study by the European Group for Blood and Marrow Transplantation. Clin Infect Dis. 2014;59:473–481.
- Teira P, Battiwalla M, Ramanathan M, et al. Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis. Blood. 2016;127:2427–2438.
- Green ML, Leisenring W, Xie H, et al. Cytomegalovirus viral load and mortality after haemopoietic stem cell transplantation in the era of pre-emptive therapy: a retrospective cohort study. Lancet Haematol. 2016;3:e119–e127.
- Marty FM, Ljungman P, Papanicolaou GA, et al. Maribavir prophylaxis for prevention of cytomegalovirus disease in recipients of allogeneic stem cell transplants: a phase 3, double-blind, placebo-controlled, randomised trial. Lancet Infect Dis. 2011;11:284–292.
- Marty FM, Ljungman P, Chemaly RF, et al. Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation. N Engl J Med. 2017;377:2433–2444.
- Goodrich JM, Bowden RA, Fisher L, Keller C, Schoch G, Meyers JD. Ganciclovir prophylaxis to prevent cytomegalovirus disease after allogeneic marrow transplant. Ann Intern Med.1993;118:173–178.
- Winston DJ, Ho WG, Bartoni K, et al. Ganciclovir prophylaxis of cytomegalovirus infection and disease in allogeneic bone marrow transplant recipients: results of a placebo-controlled, double-blind trial. Ann Intern Med. 1993;118:179–184.
- Marty FM, Boeckh M. Maribavir and human cytomegalovirus-what happened in the clinical trials and why might the drug have failed? Curr Opin Virol. 2011;1:555–562.
- Beadle JR, Hartline C, Aldern KA, et al. Alkoxyalkyl esters of cidofovir and cyclic cidofovir exhibit multiple-log enhancement of antiviral activity against cytomegalovirus and herpesvirus replication in vitro. Antimicrob Agents Chemother. 2002;46:2381–2386.
- Kern ER, Bidanset DJ, Hartline CB, Yan Z, Zemlicka J, Quenelle DC. Oral activity of a methylenecyclopropane analog, cyclopropavir, in animal models for cytomegalovirus infections. Antimicrob Agents Chemother. 2004;48:4745–4753.
- Bidanset DJ, Beadle JR, Wan WB, Hostetler KY, Kern ER. Oral activity of ether lipid ester prodrugs of cidofovir against experimental human cytomegalovirus infection. J Infect Dis. 2004;190:499–503.
- Hartline CB, Gustin KM, Wan WB, et al. Ether lipid-ester prodrugs of acyclic nucleoside phosphonates: activity against adenovirus replication in vitro. J Infect Dis. 2005;191:396–399.
- Tollefson AE, Spencer JF, Ying B, Buller RML, Wold WS, Toth K. Cidofovir and brincidofovir reduce the pathology caused by systemic infection with human type 5 adenovirus in immunosuppressed Syrian hamsters, while ribavirin is largely ineffective in this model. Antiviral Res. 2014;112:38–46.
- Williams-Aziz SL, Hartline CB, Harden EA, et al. Comparative activities of lipid esters of cidofovir and cyclic cidofovir against replication of herpesviruses in vitro. Antimicrob Agents Chemother. 2005;49:3724–3733.
- Quenelle DC, Lampert B, Collins DJ, Rice TL, Painter GR, Kern ER. Efficacy of CMX001 against herpes simplex virus infections in mice and correlations with drug distribution studies. J Infect Dis. 2010;202:1492–1499.
- Kern ER, Hartline C, Harden E, et al. Enhanced inhibition of orthopoxvirus replication in vitro by alkoxyalkyl esters of cidofovir and cyclic cidofovir. Antimicrob Agents Chemother. 2002;46:991–995.
- Quenelle DC, Collins DJ, Herrod BP, et al. Effect of oral treatment with hexadecyloxypropyl-[(S)-9-(3-hydroxy-2- phosphonylmethoxypropyl)adenine] [(S)-HPMPA] or octadecyloxyethyl-(S)-HPMPA on cowpox or vaccinia virus infections in mice. Antimicrob Agents Chemother. 2007;51:3940–3947.
- Rice AD, Adams MM, Lampert B, et al. Efficacy of CMX001 as a prophylactic and presymptomatic antiviral agent in New Zealand white rabbits infected with rabbitpox virus, a model for orthopoxvirus infections of humans. Viruses. 2011;3:63–82.
- Rice AD, Adams MM, Wallace G, et al. Efficacy of CMX001 as a post exposure antiviral in New Zealand White rabbits infected with rabbitpox virus, a model for orthopoxvirus infections of humans. Viruses. 2011;3:47–62.
- Trost LC, Rose ML, Khouri J, et al. The efficacy and pharmacokinetics of brincidofovir for the treatment of lethal rabbitpox virus infection: a model of smallpox disease. Antiviral Res. 2015;117:115–121.
- Grossi IM, Foster SA, Gainey MR, et al. Efficacy of delayed brincidofovir treatment against a lethal rabbitpox virus challenge in New Zealand White rabbits. Antiviral Res. 2017;143:278–286.
- Randhawa P, Farasati NA, Shapiro R, Hostetler KY. Ether lipid ester derivatives of cidofovir inhibit polyomavirus BK replication in vitro. Antimicrob Agents Chemother. 2006;50:1564–1566.
- Randhawa P, Zemlicka J, Sauerbrei A, et al. Anti-BK virus activity of nucleoside analogs. Antimicrob Agents Chemother. 2008;52:1519–1521.
- Bernhoff E, Gutteberg TJ, Sandvik K, Hirsch HH, Rinaldo CH. Cidofovir inhibits polyomavirus BK replication in human renal tubular cells downstream of viral early gene expression. Am J Transplant. 2008;8:1413–1422.
- Gosert R, Rinaldo CH, Wernli M, Major EO, Hirsch HH. CMX001 (1-O-hexadecyloxypropyl-cidofovir) inhibits polyomavirus JC replication in human brain progenitor-derived astrocytes. Antimicrob Agents Chemother. 2011;55:2129–2136.
- Hostetler KY. Alkoxyalkyl prodrugs of acyclic nucleoside phosphonates enhance oral antiviral activity and reduce toxicity: current state of the art. Antiviral Res. 2009;82:A84–A98.
- Painter W, Robertson A, Trost LC, Godkin S, Lampert B, Painter G. First pharmacokinetic and safety study in humans of the novel lipid antiviral conjugate CMX001, a broad-spectrum oral drug active against double-stranded DNA viruses. Antimicrob Agents Chemother. 2012;56:2726–2734.
- Aldern KA, Ciesla SL, Winegarden KL, Hostetler KY. Increased antiviral activity of 1-O-hexadecyloxypropyl-[2-(14)C]cidofovir in MRC-5 human lung fibroblasts is explained by unique cellular uptake and metabolism. Mol Pharmacol. 2003;63:678–681.
- Ciesla SL, Trahan J, Wan WB, et al. Esterification of cidofovir with alkoxyalkanols increases oral bioavailability and diminishes drug accumulation in kidney. Antiviral Res. 2003;59:163–171.
- Tippin TK, Morrison ME, Brundage TM, Momméja-Marin H. Brincidofovir is not a substrate for the human organic anion transporter 1: a mechanistic explanation for the lack of nephrotoxicity observed in clinical studies. Ther Drug Monit. 2016;38:777–786.
- Hill JA, Mayer BT, Xie H, et al. The cumulative burden of double-stranded DNA virus detection after allogeneic HCT is associated with increased mortality. Blood. 2017;129:2316–2325.
- Hill JA, Mayer BT, Xie H, et al. Kinetics of double-stranded DNA viremia after allogeneic hematopoietic cell transplantation. Clin Infect Dis. 2018;66:368–375.
- Marty FM, Winston DJ, Rowley SD, et al. CMX001 to prevent cytomegalovirus disease in hematopoietic-cell transplantation. N Engl J Med. 2013;369:1227–1236.
- Papanicolaou G, Grimley M, Morrison M, Brundage T, Mommeja-Marin H. Pre-engraftment initiation of brincidofovir (CMX001) in hematopoietic cell transplant (HCT) recipients is supported by lack of myeloid toxicity. Bone Marrow Transplant. 2014;49(S1):S327.
- Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995;15:825–828.
- Ljungman P, Griffiths P, Paya C. Definitions of cytomegalovirus infection and disease in transplant recipients. Clin Infect Dis. 2002;34:1094–1097.
- National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) v4.03. Available at: . Accessed March 17, 2018.
- Sale GE, Shulman HM, McDonald GB, Thomas ED. Gastrointestinal graft-versus-host disease in man: a clinicopathologic study of the rectal biopsy. Am J Surg Pathol. 1979;3:291–299.
- Leisenring WM, Martin PJ, Petersdorf EW, et al. An acute graft-versus-host disease activity index to predict survival after hematopoietic cell transplantation with myeloablative conditioning regimens. Blood. 2006;108:749–755.
- Kreft A, Mottok A, Mesteri I, et al. Consensus diagnostic histopathological criteria for acute gastrointestinal graft-versus-host disease improve interobserver reproducibility. Virchows Arch. 2015;467:255–263.
- Marty FM, Rubin RH. The prevention of infection post-transplant: the role of prophylaxis, preemptive and empiric therapy. Transpl Int. 2006;19:2–11.
- Razonable RR, Blumberg EA. It’s not too late: a proposal to standardize the terminology of “late-onset” cytomegalovirus infection and disease in solid organ transplant recipients. Transpl Infect Dis. 2015;17:779–784.
- GB McDonald. How I treat acute graft-versus-host disease of the gastrointestinal tract and the liver. Blood. 2016;127:1544–1550.
- Papadimitriou JC, Cangro CB, Lustberg A, et al. Histologic features of mycophenolate mofetil-related colitis: a graft-versus-host disease-like pattern. Int J Surg Pathol. 2003;11:295–302.
- Selbst MK, Ahrens WA, Robert ME, Friedman A, Proctor DD, Jain D. Spectrum of histologic changes in colonic biopsies in patients treated with mycophenolate mofetil. Mod Pathol. 2009;22:737–743.
- Detweiler CJ, Mueller SB, Sung AD, Saullo JL, Prasad VK, Cardona DM. Brincidofovir (CMX001) toxicity associated with epithelial apoptosis and crypt drop out in a hematopoietic cell transplant patient: challenges in distinguishing drug toxicity from GVHD. J Pediatr Hematol Oncol. 2018;40:e364–e368.
- U.S. National Library of Medicine. SUSTAIN: a randomized, double-blind, multicenter, phase 3 study of the efficacy, safety, and tolerability of brincidofovir versus valganciclovir for the prevention of cytomegalovirus disease in CMV seronegative kidney allograft recipients (BCV CMV vGCV). Available at: . Accessed April 3,2018.
- Wire M, Anderson M, Arumugham T, Morrison M, Dunn J, Naderer O. Co-administration of cyclosporine (CsA) increases plasma brincidofovir (BCV) exposure in healthy volunteers. Pharmacotherapy. 2016;36:e269.
- Niemi M, Pasanen MK, Neuvonen PJ. Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev. 2011;63:157–181.
- Karlgren M, Vildhede A, Norinder U, et al. Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions. J Med Chem. 2012;55:4740–4763.
- Florescu DF, Pergam SA, Neely MN, et al. Safety and efficacy of CMX001 as salvage therapy for severe adenovirus infections in immunocompromised patients. Biol Blood Marrow Transplant. 2012;18:731–738.
- Grimley MS, Marsh RA, Bleesing JJ, et al. Cmx001 as therapy for severe adenovirus infections in immunocompromised pediatric patients: single experience in 5 patients. Biol Blood Marrow Transplant. 2012;18:S315.
- Chittick G, Morrison M, Brundage T, Nichols WG. Short-term clinical safety profile of brincidofovir: a favorable benefit-risk proposition in the treatment of smallpox. Antiviral Res. 2017;143:269–277.
- Grimley MS, Chemaly RF, Englund JA, et al. Brincidofovir for asymptomatic adenovirus viremia in pediatric and adult allogeneic hematopoietic cell transplant recipients: a randomized placebo-controlled phase II trial. Biol Blood Marrow Transplant. 2017;23:512–521.
- Ramsay ID, Attwood C, Irish D, Griffiths PD, Kyriakou C, Lowe DM. Disseminated adenovirus infection after allogeneic stem cell transplant and the potential role of brincidofovir: case series and 10-year experience of management in an adult transplant cohort. J Clin Virol. 2017;96:73–79.
- Hiwarkar P, Amrolia P, Sivaprakasam P, et al. Brincidofovir is highly efficacious in controlling adenoviremia in pediatric recipients of hematopoietic cell transplant. Blood. 2017;129:2033–2037.
- Saffrey MJ. Aging of the mammalian gastrointestinal tract: a complex organ system. Age (Dordr). 2014;36:9603.
- Wire MB, Morrison M, Anderson M, Arumugham T, Dunn J, Naderer O. Pharmacokinetics (PK) and safety of intravenous (IV) brincidofovir (BCV) in healthy adult subjects. Open Forum Infect Dis. 2017;4(Suppl 1). S311.
Source: PubMed